ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4883T>C (p.Met1628Thr) (rs4986854)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112415 SCV000244371 benign Breast-ovarian cancer, familial 1 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000495. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.01399 (Asian), derived from 1000 genomes (2012-04-30).
Invitae RCV001084481 SCV000076696 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000112415 SCV000154024 likely benign Breast-ovarian cancer, familial 1 2014-03-07 criteria provided, single submitter literature only
Ambry Genetics RCV000162565 SCV000212978 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000120263 SCV000219252 benign not specified 2016-12-29 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000112415 SCV000267716 benign Breast-ovarian cancer, familial 1 2016-04-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000120263 SCV000538434 likely benign not specified 2016-03-29 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.8% (51/6614) Finnish; ClinVar: 6 B/LB
Color Health, Inc RCV000162565 SCV000683224 benign Hereditary cancer-predisposing syndrome 2014-12-30 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000112415 SCV000743386 benign Breast-ovarian cancer, familial 1 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000112415 SCV000744606 benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034754 SCV000806963 likely benign not provided 2017-08-03 criteria provided, single submitter clinical testing
Mendelics RCV000112415 SCV001140506 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112415 SCV001287202 benign Breast-ovarian cancer, familial 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287100 SCV001473746 benign none provided 2020-03-12 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034754 SCV000043155 probably not pathogenic not provided 2012-07-13 no assertion criteria provided research Converted during submission to Likely benign.
ITMI RCV000120263 SCV000084415 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000112415 SCV000145201 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148381 SCV000190079 likely benign Breast neoplasm 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353702 SCV000591545 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Met1628Thr variant was identified in at least 105 of 111464 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer, and was present in 55 of 1140 control chromosomes (frequency: 0.048) (Inoue 1995, Judkins 2005, Ostrow 2004, Phelan 2004, Tavtigian 2006, Tamboom 2010). The variant was listed in dbSNP (ID: rs4986854) “With untested allele”, with a minor allele frequency of 0.004 (1000 Genomes Project); in HapMap-JPT cohort with a frequency of 0.041, and the PAC1 cohort with a frequency of 0.21; and Inoue (1995) found the variant allele at a frequency of 0.39 in a Japanese group of healthy control individuals. The identification of the variant in these population cohorts increases the likelihood that this is a low frequency benign variant in certain populations of origin. The variant was also identified in HGMD, LOVD, the BIC database (96X with unknown clinical importance), and UMD (4X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.4576dup (p.Thr1526AsnfsX3)), and Judkins (2005) observed the variant in trans with three different pathogenic BRCA1 mutations, increasing the likelihood that the p.Met1628Thr variant does not have clinical significance. In addition, a study by Phelan (2004) found that the variant did not segregate with disease in one family, and two functional studies showed no showed no effect of the variant on transcriptional activation (Phelan 2004, Ostrow 2004). Furthermore, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
True Health Diagnostics RCV000162565 SCV000787906 likely benign Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing

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